Due to its extensive history of safety as well as availability in multiple tumor types, lethally irradiated tumor cell vaccines engineered to secrete GM-CSF (GVAX) is one vaccine platform that has potential for combinatorial therapy with immune checkpoint blockade antibodies. However, local GM-CSF secreted by GVAX can mobilize myeloid precursors into macrophages and dendritic cells, but this cytokine may not induce their activation. Thus, a major limitation of GVAX is in the activation of antigen presenting cells (APC) necessary for optimal tumor antigen presentation in the afferent arm of the immune system. One simple strategy that phenocopies the robust immunological responses seen in vaccines against infectious agents is to combine multiple TLR agonists with a cancer cell-based vaccine. Clinically, multiple adjuvants have been developed for cancer patients to augment the potency of cancer vaccines, and many of these adjuvants are typically TLR agonists.
One real concern with non-targeted TLR stimulation is the procarcinogenic consequences of chronic TLR stimulation in the tumor cells. Stimulation of TLR4 receptors expressed on tumor cells has shown to promote carcinogenesis. TLR signaling in the hematopoietic compartment, however, has been shown to elicit anti-tumor responses, which have translated into multiple clinical trials. In order to target the dendritic cells in the tumor microenvironment and test whether TLR4 stimulation in the tumor microenvironment can induce a procarcinogenic effect in vivo, our group injected LPS formulated GVAX intratumorally and found that intratumoral injection of TLR4 ligand absorbed GVAX improved the local anti-tumor response in vivo in three different murine models.
There is a continuing need in the art to obtain safer and more effective treatments of tumors.